1. Field of the Invention
The present invention relates generally to protection of the immune system. More particularly, it concerns preventing or correcting immunological damage to skin exposed to ultraviolet irradiation.
2. Description of Related Art
Recent reports directed to the global depletion of ozone in the atmosphere, including the discovery of the Antarctic "hole" in the ozone layer, have focused interest in the effects of ultraviolet radiation on human health. Although some exposure to ultraviolet radiation is needed for humans to produce vitamin D, the evidence overwhelmingly shows that ultraviolet radiation exposure is related to a range of health problems. Specifically, it is well known that ultraviolet exposure causes sunburn and is involved in the induction of certain skin cancers.
In addition to these established health concerns, research has provided recent evidence suggesting that exposure to ultraviolet radiation may have detrimental effects upon a variety of immunological reactions and may decrease the immune system's ability to respond to various infectious agents. See, e. g., Kripke (1990). In particular, it is thought that ultraviolet radiation-induced injury to the skin immune system supplies a second factor necessary for the development of common skin cancers. The primary factor in the induction of skin cancer is the mutational damage done by ultraviolet radiation to the DNA of the generative cells in the skin. However these early malignant cells are thought to be eliminated by the normal functioning of the skin immune system. When the immune function of the cells in the skin is suppressed by ultraviolet radiation, the cells cannot perform their usual surveillance function and eliminate very early skin cancers.
The effect of ultraviolet radiation in suppressing the skin immune system is separate and dissociable from the grossly apparent inflammatory and irritant effects of ultraviolet radiation on the skin such as erythema (redness), edema (swelling), and hyperkeratosis (flaking or scaling). Modalities taught in the prior art for the prevention and treatment of skin inflammation and irritation do not appear to be of utility in the treatment of ultraviolet-light-induced suppression of the skin immune system. For example, Reeve et al. (1991) reported that topical application of certain ultraviolet radiation-absorbing compounds, such as certain sunscreens, were effective in preventing ultraviolet radiation-induced erythema and edema, but that some of these sunscreens failed to prevent immunosuppression in a mouse model as measured either by contact hypersensitivity or by induction of susceptibility to transplanted tumor cells. Thus prevention of irritation and inflammation did not prevent suppression of the skin immune system. This was confirmed by Von Praag et al. (1991) and Wolf et al. (1994), who reported that commercial sunscreens may not fully protect against ultraviolet radiation-induced immunological alterations. Indirect evidence for this idea was presented by Vermeer et al. (1991) by studying the immune reaction of human subjects to the contact allergen dinitrochlorobenzene. They concluded that the pigmentation levels (of either dark skinned or tanned subjects) did not appear to protect the skin immune system from the damaging effects of ultraviolet radiation (although it is well accepted that skin pigmentation protects the skin against the irritant and inflammatory effects of ultraviolet radiation).
These studies suggest that while sunscreens alone do prevent inflammation and irritation they do not provide complete prophylactic protection against the immunosuppressive effects of ultraviolet radiation. Furthermore, pharmacologic agents which are commonly and traditionally employed for the treatment of irritated and inflamed skin are without effect in treating the suppression of the skin immune system induced by exposure to ultraviolet radiation when they are applied after the injury is manifest. Andersen et al. (1992) examined in humans the effect of treatment with the four commonest anti-inflammatory agents of ultraviolet radiation-injured skin upon edema and erythema. Topically applied corticosteroids were most effective in reducing inflammation and irritation, followed respectively by indomethicin, acetylsalicylic acid (aspirin), and diphenhydramine (Benadryl.RTM.). Aspirin and Benadryl.RTM. have not been demonstrated to be capable of restoring the ultraviolet radiation-induced damage to the skin immune system. Local application of corticosteroids reduces the skin immune response, as taught by Bergstresser (1989) and many others. Although indomethacin has been demonstrated by Reeve et al. (1995) to inhibit photocarcinogenesis, this effect appears to involve both the initiation period and the promotion period of tumor development and thus is thought to be a function of a generalized anti-carcinogenesis effect rather than an effect on the skin immune system. Thus there appears to be a pattern whereby agents capable of suppressing inflammation and irritancy do not protect the skin immune system. Recognizing this dissociation of the phenomenon of inflammation/irritation from the induction of skin cancer, academic experimental dermatologists have virtually abandoned the use of erythema and edema as endpoints for the deleterious effects of ultraviolet radiation in the induction of skin cancer, and have instead adopted direct measures of carcinogenesis (e. g., mutational changes in the DNA of skin cells and direct measurement of the function of the skin immune system).
Several investigators have noted the anti-inflammatory and anti-irritant activities of Aloe materials. For example, Farkas (U.S. Pat. No. 3,103,466) disclosed the use of Aloe Vera to provide analgesic effect upon inflammed or irritated skin. However, these investigators failed to demonstrate an understanding of the difference between treatment of inflammation and irritation versus restoration of the skin immune response. For example, some inventors have viewed Aloe preparations as having utility only as sunscreens (see Baron, U.S. Pat. No. 4,788,007) and thus having utility only for prevention and not for treatment. Those inventors which appreciate the ultility of Aloe preparations for theraputic purposes seem to envision only effects that can be seen (erythema and swelling) or percieved (itching and pain). For example, those patents which directly claim relief of pain and itching (Rosenthal, U.S. Pat. No. 4,585,656 and Gruber, U.S. Pat. No. 4,593,046) offer embodiments that result in products that may be ineffective in restoring the skin immune system. Those patents concerned with processing (Maret, U.S. Pat. No. 3,878,197; Cobble, U.S. Pat. No. 3,892,853 and Coats, U.S. Pat. No. 4,178,372) which do not claim biological activity but which do refer to biological activity in the examples teach little to one skilled in the art; the examples are so vague with regard to biological activity on topical application that one would not be led to understand the difference between the treatment of inflammation and irritation versus restoration of the skin immune system. Therefore, it is not suprising that commercial Aloe products are ineffective in preventing suppression of the skin immune response by ultraviolet radiation.
Strickland et al. (1994) have investigated the ability of Aloe barbadensis gel extract to prevent suppression of contact hypersensitivity (CHS) and delayed-type hypersensitivity (DTH) responses in mice by ultraviolet (UV) radiation. Treatment of UV-irradiated skin with Aloe immediately after irradiation was found to prevent suppression of both CHS to fluorescein isothiocyante and DTH to Candida albicans. Aloe treatment did not prevent the formation of cyclobutyl pyrimidine dimers in the DNA of UV-irradiated skin or accelerate repair of these lesions. Thus, these studies demonstrated that topical application of an Aloe barbadensis gel extract to the skin of UV-irradiated mice ameliorates UV-induced immune suppression by a mechanism other than DNA damage or repair. However, the precise components of Aloe gel having these beneficial effects were not identified. Strickland et al. also noted that there can be marked variability with regard to sources of Aloe, variability in commercial Aloe gel extract production processes, and variability with regard to bacteriology of starting materials, all of which can contribute to the difficulty of obtaining consistent, reproducible data in studies of the biological activity of Aloe extracts. Byeon et al. (1998) have shown that Aloe contains multiple immunoprotective factors, some of which are labile, i. e., their ability to prevent immunosuppression can decay rapidly following manufacture.
Strickland et al. in U.S. Pat. No. 5,824,659 teach that the Aloe polysaccharide in its native form is biologically inactive. Upon cleavage by a crude culture supernatant of fungi termed "cellulase," this heteropoylsaccharide is cleaved into two chemically and biologically distinct fragments. The first fragment termed acemannan by McAnalley has the biological activity classically ascribed to Aloe polysaccharide, physically consists of polymers ranging in molecular weight from greater than 5,000 daltons to greater than 200,000 daltons, and chemically consists of repeating units of beta 1-4 mannan alternately 6 and 2-3 acetylated. The second product of "cellulase" cleavage consists of branch points forming the acemannan homopolymer into a gel, physically comprises oligosaccharide of under 5,000 daltons molecular weight, and chemically consists of glucose more so than mannose comprising 1, 4, and 6 linkages. U.S. Pat. No. 5,824,659 further teaches that it is this cleavage oligosaccharide which bears the cytoprotective biological activity, especially the ability to downregulate Interleukin-10 production by UVB-injured keratinocytes. U.S. Pat. No. 5,824,659, however, is silent with regard to various aspects of the present invention, which allow for maximal benefit to be derived from the invention. For example, the fresh Aloe barbadensis used in U.S. Pat. No. 5,824,659 is difficult to obtain commercially with desired purity and freshness (Pelley et al., Subtropical Plant Science 1999). Furthermore, U.S. Pat. No. 5,824,659 teaches that the cytoprotective oligosaccharide used in that patent is subject to further inactivating cleavage by glycosidases. Furthermore, U.S. Pat. No. 5,824,659 is silent as to how those of ordinary skill in the art could predictably find plant oligosaccahrides similar to those taught in that application and how compounds of greater potency than those taught in U.S. Pat. No. 5,824,659 may be obtained.
Clearly, there exists a need for an effective method or treatment modality for preventing or correcting immunological damage to skin exposed to ultraviolet irradiation. Such a method would ideally employ a composition including a well-characterized active ingredient having excellent chemical stability and long shelf life.